Project Summary: Head and neck squamous cell carcinoma (HNSCC) is thought to be caused by the effects of environmental carcinogens including tobacco, alcohol, betel quid, organic solvents, coal dust, welding fumes, asbestos, and polycyclic aromatic hydrocarbons. The morbidity and mortality associated with HNSCC largely stem from its invasiveness and the high incidence of second primary tumors (SPTs), which are thought to result from "field carcinogenesis," molecular changes in the histologically normal tissue surrounding the primary tumor. Chemoprevention, aimed at counteracting the effects of carcinogens and/or preventing HNSCC SPTs and recurrence, is an important goal. We hypothesize that guggulsterone, a plant- derived compound, may be efficacious as a preventive therapy for HNSCC. Guggulsterone, known for its cholesterol-lowering activity, is available in clinical formulations as a dietary supplement. It has been shown to having anticancer activity in prostate cancer, acute myeloid leukemia, lung cancer and breast cancer cells and, additionally, to suppress the activity of nuclear factor KB (NFKB), a transcription factor that promotes tumorigenesis in HNSCC and other cancers. Our preliminary studies show that treatment of human HNSCC cells with guggulsterone results in growth inhibition, apoptosis, cell cycle arrest and decreases in total and phosphotyrosine (activated) Signal Transducer and Activator of Transcription (STAT)-3, an oncogenic transcription factor known to be constitutively active in most HNSCC tumors. This study will explore the molecular mechanisms of guggulsterone's anticancer activity through in vitro investigation of changes in levels of cell-cycle-promoting and anti-apoptotic genes that are also targets for STATS and NFKB. The mechanism behind the guggulsterone-induced decrease in STATS levels will also be explored. Finally, guggulsterone's chemopreventive effects will be investigated in vivo through the use of two mouse models of HNSCC, a xenograft model and an inducible TGF(3 receptor II deletion/K-Ras mutant, which develops HNSCC tumors similar to those seen in humans. The goal of this work will be to ascertain whether or not guggulsterone may be used for Chemoprevention of HNSCC and to elucidate the molecular mechanism behind guggulsterone's anticancer activity, thus providing a firm basis for its future use in clinical trials. Relevance: HNSCC is an extraordinarily devastating disease and the sixth most common cancer worldwide. Because it is a disease caused by environmental exposures and because high levels of HNSCC- associated morbidity and mortality result from second primary tumors and recurrence, methods of preventing HNSCC have the potential to make a great impact on public health.